This invention relates to novel inhibitors of sex steroid activity such as antiestrogen compounds having effective antagonistic capability while substantially lacking agonistic effects. More particularly, certain preferred embodiments of the invention relate to certain estradiol and non-steroidal diphenylethylene analogs which have high affinity for estrogen receptors but do not activate such receptors and/or which inhibit the production of sex steroids or their precursors.
During the treatment of certain sex steroid-dependent diseases, it is important to greatly reduce or, if possible, eliminate certain sex steroid-induced effects. For this purpose, it is desirable both to block receptor sites stimulated by sex steroids and also to reduce the amount of sex steroid available to act at these sites. For example, alternative or concurrent therapy to administration of antiestrogens could involve attempts to block the production of estrogens (e.g. by ovariectomy) such that less is available to activate receptor sites. However, prior art methods for blocking estrogen production insufficiently inhibit estrogen-induced functions. Moreover, it is possible that even in the total absence of sex steroids, unoccupied sex steroid receptors may be biologically active. Hence, antagonists of sex steroids may produce greater therapeutic results than therapy which only inhibits sex steroid production. Prior art antagonists, however, often have insufficient affinity for receptors, and some, although capable of binding the receptors, may themselves act as agonists and undesirably activate some receptors and induce the same effects as a sex steroid.
There is, therefore, a need in the art for antiestrogens which effectively block estrogen receptors with minimal or no agonistic effect. Numerous compounds have been tried in the art with mixed results. Known antiestrogens continue to exhibit undesirable agonistic activity. See, for instance, Wakeling and Bowler, "Steroidal Pure Antioestrogens", J. Endocrinol. (1987) 112, R7-R10. The net effectiveness of prior art compounds is determined by the balance between their agonistic and antagonistic activities. Certain steroidal derivatives similar to those disclosed in the foregoing article, and which are stated to have antioestrogenic effect, are set forth in Bowler et al., U.S. Pat. No. 4,659,516.
In U.S. Pat. No. 4,094,994, it is disclosed that the use of certain antiestrogens may inhibit certain human breast tumor cells.
H. Mooridsen et al., Cancer Treatment Review 5, 131-141, (1978), discloses that Tamoxiphen, an antiestrogen, is effective in remission of advanced breast cancer in about 30 percent of the women patients treated.
The combined use of the antiestrogen Tamoxiphen and a luteinizing hormone-releasing hormone agonist, Buserelin, is also known for treatment of breast cancer. See, for instance, Klijn et al., J. Steroid Biochem, 420, No. 6b, 1381 (1984): The objective remission of such cancers, however, remains unacceptably low.
It has been found that certain 7.alpha.-substituted derivatives of estradiol possess antiestrogenic activity (Bowler et al., 1985; Eur. Patent Application 0138504; Wakeling and Bowler, J. Steroid Biochem. 30; 141-147, 1988).
In U.S. Pat. No. 4,659,516, Bowler et al. report antiestrogenic activity for certain 7.alpha. substituted derivatives of estradiol.
For a number of years, there has been research for compounds which can efficiently inhibit androgen and/or estrogen formation (e.g. enzyme inhibitors) or for compounds which may suppress androgen or estrogen action (steroid antagonists), without causing adverse effects to healthy tissues.
Recently, estradiol derivatives bearing a carboxyalkyl substituent at the 7.alpha.-position maintained their affinity for the estrogen receptor when linked via their carboxy group to agarose or polyacrylamide resin for affinity chromatography purification of the estrogen receptor (Bucourt et al., J. Biol. Chem. 253: 8221, 1978).
Non steroidal compounds bearing a similar aliphatic side chain have also been found to possess antiestrogenic activity (U.S. Pat. No. 4,732,912).
Some steroid derivatives, such as especially 16-methylene estradiol and 16-methylene estrone, have been described as inhibitors of 17.beta.-hydroxysteroid dehydrogenase activity (Thomas et al., J. Biol. Chem. 258: 11500, 1983).
Prior art methods have not been completely effective in inhibiting sex steroid synthesis while avoiding undesirable side effects.
Certain nonsteroidal compounds which are stated to have antiandrogenic effect are described by Furr et al., J. Endocr. 113, R7-R9, 1987.
In U.S. Pat. No. 4,659,695 relates to a method of treatment of prostate cancer for susceptible male animals including humans whose testicular hormonal secretions are blocked by surgical or chemical means, e.g., by use of an LHRH agonist, e.g., [D-Trp.sup.6, des-Gly-NH.sub.2.sup.10 ]LHRH ethylamide. The treatment includes administering an antiandrogen, e.g., flutamide in association with at least one inhibitor of sex steroid biosynthesis, e.g., aminoglutethimide and/or ketoconazole.
U.S. Pat. No. 4,472,382 relates to a method of treating prostate cancer using the combination of an antiandrogen and an LHRH agonist.
In U.S. Pat. No. 4,386,080 relates to new amide derivatives, and more particularly novel acylanilides, possess antiandrogenic properties.
In French, Patent 2528434 and in Jordan and Koch, "Regulation of Prolactin Synthesis in vitro by estrogenic and antiestrogenic derivatives of estradiol and Estrone", Endocrinology 124(4): 1717-1725 (1989), antiestrogenic effects are described for certain 11.beta.-long chain substituted estradiol derivatives.
In U.S. Pat. No. 3,995,060, U.S. Pat. No. 4,161,540 and U.S. Pat. No. 4,139,638, it is disclosed that certain 4'-substituted and 3'-, 4'-disubstituted anilides have antiandrogenic properties.
EP Pat. No. 138 504, EP Pat. No. 166 509, EP Pat No. 124 369, EP Pat. No. 160 508, EP Pat. No. 163 416, U.S. Pat. No. 4,732,912, U.S. Pat. No. 4,760,061, U.S. Pat. No. 4,751,240, U.S. Pat. No. 4,659,516 and Wakeling A. E. and Bowler J., J. Endocr. 112, R7-R10, 1987., and J. Steroid Biochem. 30, 141-147, 1988 disclose that certain long chain substitutions onto an estrogenic nucleus may result in compositions exhibiting antiestrogenic activity.
For a number of years, there has been search for compounds which can efficiently inhibit androgen and/or estrogen formation without causing adverse effects to healthy tissues. More particularly, the inhibition of 17.beta.-hydroxysteroid dehydrogenase, which is involved in the biosynthesis of testosterone, androst-5-ene-3.beta.,17.beta.-diol and estradiol, has been studied by some workers. Some affinity-label inhibitors for human placental estradiol 17.beta.-dehydrogenase have been described (C. C. Chin and J. C. Warren, J. Biol. Chem. 250, 7682-7686, 1975; Y. M. Bhatnagar et al., J. Biol. Chem. 253, 811-815, 1978; C. C. Chin et al., J. Biol. Chem. 255, 3660-3664, 1980; J. L. Thomas and R. C. Strickler, J. Biol. Chem. 258, 1587-1590, 1983).
B. Tobias et al., J. Biol. Chem. 257, 2783-2786, 1982 and R. J. Auchus and D. F. Covey, Biochemistry 25, 7295-7300, 1986 disclose, respectively, the use of 17.beta.-propynyl-substituted progestins and propynyl-substituted 3-hydroxy-14,15-secoestra-1,3,5(10)-trien-17-one as inhibitors of the 17D-estradiol dehydrogenase.
Thomas J. L. et al., J. Biol. Chem. 258, 11500, 1983 have described that 16-methylene estradiol and 16-methylene estrone are inhibitors of 17.beta.-hydroxysteroid dehydrogenase activity.